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WO2002003991A2 - Methodes permettant d'accroitre l'activite d'oxyde nitrique- synthase - Google Patents

Methodes permettant d'accroitre l'activite d'oxyde nitrique- synthase Download PDF

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Publication number
WO2002003991A2
WO2002003991A2 PCT/US2001/021083 US0121083W WO0203991A2 WO 2002003991 A2 WO2002003991 A2 WO 2002003991A2 US 0121083 W US0121083 W US 0121083W WO 0203991 A2 WO0203991 A2 WO 0203991A2
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Prior art keywords
alkyl
phenyl
hydroxy
alkylamino
group
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PCT/US2001/021083
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English (en)
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WO2002003991A3 (fr
Inventor
Steven Jay Adelman
Thomas Michaell Argentieri
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Wyeth
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Application filed by Wyeth filed Critical Wyeth
Priority to JP2002508445A priority Critical patent/JP2004502734A/ja
Priority to EP01950824A priority patent/EP1296674A2/fr
Priority to BR0112360-2A priority patent/BR0112360A/pt
Priority to CA002414111A priority patent/CA2414111A1/fr
Priority to AU7178301A priority patent/AU7178301A/xx
Priority to MXPA02012890A priority patent/MXPA02012890A/es
Publication of WO2002003991A2 publication Critical patent/WO2002003991A2/fr
Publication of WO2002003991A3 publication Critical patent/WO2002003991A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to methods of using substituted indole compounds to increase or maintain nitric oxide synthesis in a mammal, preferably in a human. More particularly, this invention relates to methods of using substituted indole compounds to increase or maintain nitric oxide synthase activity and the output of nitric oxide from endothelial cells.
  • Nitric oxide acts as a regulator in the cardiovascular, intestinal, central nervous, and immune systems. Biologically, it is involved in a variety of actions including neurotransmission, vasodilation, cytotoxicity of macrophages and inhibition of platelet aggregation. It is synthesized from L-arginine by enzymes known as NO synthase (NOS).
  • NOS NO synthase
  • the calcium dependent form of NOS ' produced in vascular endothelial cells, referred to as eNOS has been indicated to be regulated through concentrations of estrogen.
  • Estrogen has been indicated in the up-regulation of eNOS m-RNA production and the subsequent endothelial cell synthesis of eNOS. This increased eNOS level allows the endothelial cells to produce more NO in response to relevant vascular system stimuli.
  • nitric oxide acts to inhibit platelet aggregation, inflammatory cell adhesion, as well as smooth muscle cell proliferation. It is also a regulator of smooth muscle and vascular tone, playing an essential role in regulation of blood pressure. It is also indicated in preventing oxidative modification of low- density lipoprotein (LDL), which contributes to atherosclerosis, particularly in its oxidized form.
  • LDL low- density lipoprotein
  • EP 0 802 183 A 1 and U.S. Patent No. 5,780,497 describe substituted indole compounds of the formulae below: as well as their use as estrogenic agents, including the treatment of bone loss, cardiovascular disease, maladies associated with or resulting from the proliferation or abnormal development of endometrial or endometrial-like tissues, and disease states or syndromes associated with estrogen deficiency.
  • This invention comprises methods of increasing or maintaining nitric oxide synthesis in a mammal, preferably in a human, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formulae I or II, below:
  • R. ! is selected from H, OH or the C1-C1 2 esters (straight chain or branched) or
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the C1-C1 2 esters
  • R2 is not OH
  • R is selected from H, OH or the C1-C1 2 esters (straight chain or branched) or C,-C 12 alkyl ethers (straight chain or branched or cyclic) thereof, benzyloxy, halogens, or C C 4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, alkyl (straight chain or branched), or trifluoromethyl;
  • X is selected from H, C1-C6 alkyl, cyano, nitro
  • R 7 and Rs are independently selected from the group of H
  • C1-C6 alkyl or phenyl optionally substituted by CN, -C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, -OH,
  • R 7 and R 8 are combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, Ci- C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C4)alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di-(C ⁇ - C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C )alkyl and
  • a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(C ⁇ .C4 alkyl)-, -N , and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C ⁇ -C alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C1-C4 alkylsulfinyl, Ci- alkylsulfi yl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H-, -CN-, -CONHR,, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alky
  • a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(C ⁇ _C alkyl)-, -N , and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C ⁇ -C4alko y, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C ⁇ -C alkylsulfinyl, C ⁇ -C 4 alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H-, -CN-, -CONHR,-, -NH 2 , C1-C4 alkylamino, di(C ⁇ -C 4 )al
  • a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(C ⁇ _C4alkyl)-, -N , and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy (C ⁇ -C4)alkyl, -CO 2 H-, -CN-, -CONHR,, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )al
  • a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing up to two heteroatoms selected from the group consisting of -O-, -NH-, ⁇ N(Ci-G4alkyl)-, and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C1-C4 alkylsulfmyl, C ⁇ -C 4 alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN,
  • R x is selected from H, OH or the C -C1 2 esters or alkyl ethers thereof, halogen;
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the C1-C1 2 esters or alkyl ethers thereof, halogen, cyano, Ci-C ⁇ alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R 2 is not OH;
  • R 4 is selected from H, OH or the -C1 2 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, -C6 alkyl, or trihalomethyl;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety
  • R 7 and R 8 are selected independently from H, C ⁇ C alkyl, or combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C4)alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, diC ⁇ -C 4 alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl, and
  • the rings formed by a concatenated R7 and Rs, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
  • the most preferred compounds of the present invention are those having the structural formulas I or II, above, wherein Rj is OH; R 2 - R ⁇ are as defined above; X is selected from the group of Cl, NO2, CN, CF3, or CH3; and Y is the moiety
  • R7 and Rs are concatenated together as -(CH2)r, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl, and -NO 2 ; and the pharmaceutically acceptable salts thereof.
  • R7 and Rs are concatenated together as -(CH2)p-, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing C1-C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the invention includes sulfate, sulfamates and sulfate esters of phenolic groups.
  • Sulfates can be readily prepared by the reaction of the free phenolic compounds with sulfur trioxide complexed with an amine such as pyridine, trimethylamine, triethylamine, etc.
  • Sulfamates can be prepared by treating the free phenolic compound with the desired amino or alkylamino or dialkylamino sulfamyl chloride in the presence of a suitable base such as pyridine.
  • Sulfate esters can be prepared by reaction of the free phenol with the desired alkanesulfonyl chloride in the presence of a suitable base such as pyridine.
  • this invention includes compounds containing phosphates at the phenol as well as dialkyl phosphates.
  • Phosphates can be prepared by reaction of the phenol with the appropriate chlorophosphate.
  • the dialkylphosphates can be hydrolyzed to yield the free phosphates.
  • Phosphinates are also claimed where the phenol is reacted with the desired dialkylphosphinic chloride to yield the desired dialkylphosphinate of the phenol.
  • the invention includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid useful as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
  • this invention includes quaternary ammonium salts of the compounds herein. These can be prepared by reacting the nucleophilic amines of the side chain with a suitably reactive alkylating agent such as an alkyl halide or benzyl halide.
  • the methods of this invention particularly include methods of increasing or maintaining endothelial derived nitric oxide levels in a mammal, preferably in a human, the method comprising administering to the mammal a pharmaceutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically effective amount of the compound will be understood to be a dosage amount which will lead to an increase in vascular nitric oxide levels. This increase in nitric oxide concentration may be utilized to treat the physiological conditions related to nitric oxide levels, including diabetes, stroke, atherosclerosis, and hypertension, including pulmonary hypertension.
  • This invention may also be characterized as providing methods for increasing the nitric oxide synthase (NOS) activity in a mammal, particularly the endothelial base NOS activity.
  • NOS nitric oxide synthase
  • This invention includes methods of increasing nitric oxide levels in a mammal to inhibit, limit or prevent oxidative modification of low-density lipoprotein (LDL), thus reducing the LDL's ability to contribute to atherosclerosis and related vascular maladies, including hypertension and stroke.
  • LDL low-density lipoprotein
  • nitric oxide in mammalian vasculature provides to a control, prevention, or inhibition of atherogenic processes, including monocyte adhesion to endothelial surfaces, platelet aggregation, vascular smooth muscle cell proliferation, and vasoconstriction.
  • Administration of one or more compounds of this invention will be understood to be of considerable utility for prophylactic or therapeutic administration to those with an abnormally low level of NOS activity, particularly those subject to hypertension or an elevated risk of pulmonary hypertension, ischemic stroke, heart failure, progressive renal disease, thrombosis, myocardial infarction, reperfusion injury, or a nervous system degenerative disorder, such as Alzheimer's disease, or those chronically exposed to hypoxic conditions.
  • the present invention includes methods utilizing a first subset or subgroup of compounds of the formulas III or IV, below:
  • variable substituents including R, R 2 , R 3 , R 4 , R 5 , R 6 , n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
  • the more preferred compounds of this first subset of compounds are those having the general structures IH or IV, above, wherein:
  • Ri is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, or halogen;
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the C1-C12 esters or alkyl ethers thereof, halogen, cyano, C1-C6 alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
  • R is selected from H, OH or the C1-C1 2 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C1-C6 alkyl, or trihalomethyl;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen;
  • Y is the moiety
  • R 7 and R 8 are selected independently from H, C1-C6 alkyl, or combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, - C4alkylthio, C ⁇ -C 4 alkylsulfinyl, Ci- idkylsulfonyl, hydroxy(C ⁇ -C4)alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )a ⁇ lkyl, -NH 2 , C ⁇ -C 4 alkylamino, diC ⁇ -C 4 alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl,
  • the most preferred compounds of this first subset of compounds are those having the structural formulas I or II, above, wherein Ri is OH; R2 - Re are as defined above; X is selected from the group of Cl, NO2, CN, CF 3 , or CH3; and Y is the moiety
  • R 8 and R7 and Rs are concatenated together as -(CH2)r, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl and -NO 2 ; and the pharmaceutically acceptable salts thereof
  • this first subset of compounds when R7 and Rs are concatenated together as -(CH2)p-, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing C1-C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the compounds of this first subset or subgroup of compounds can be produced by the methods described in EP 0 802 183 Al, published October 22, 1997, and U.S. Patent No. 5,780,497, the subject matter of which is incorporated herein by reference, or by other methods known in the art.
  • Aryloxy-alkyl-dialkylamines or aryloxy-alkyl-cyclic amines useful as intermediates in the production of the compounds above can be produced and used as disclosed in WO 99/19293, published April 22, 1999, the subject matter of which is also incorporated herein by reference.
  • a second subset or subgroup of compounds useful with this invention includes those of formulas (V) or (VI), below:
  • variable substituents including R, R 2 , R 3 , R 4 , R 5 , R 6 , n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
  • n 1, 2 or 3 and the variable substituents including R, R 2 , R 3 , R 4 , R 5 , R 6 , n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compounds of this third subset or subgroup of compounds can be produced by the methods described in U.S. Patent No. 5,880,137 (Miller et al.), which is incorporated herein by reference, or by other methods known in the art.
  • Ri is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, halogen;
  • R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from H, OH or the C1-C1 2 esters or alkyl ethers thereof, halogen, cyano, C1-C6 alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R 2 is not OH;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety
  • R 7 and R 8 are selected independently from H, Ci-C ⁇ alkyl, or combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, Ci-C ⁇ alkoxy, trihalomethoxy, C -
  • the rings formed by a concatenated R7 and Rs, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
  • the most preferred compounds of the present invention are those having the structural formulas I through VIE, above, wherein Ri is OH; R2 - R6 are as defined above; X is selected from the group of Cl, NO2, CN, CF3, or CH 3 ; and Y is the moiety
  • R 8 and R7 and Rs are concatenated together as -(CH2)r, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, -C4 alkoxy, trihalomethoxy, C ⁇ -C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl, and -NO 2 ; and the pharmaceutically acceptable salts thereof
  • R7 and Rs are concatenated together as -(CH 2 )p-, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing C 1 -C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the invention includes sulfate, sulfamates and sulfate esters of phenolic groups.
  • Sulfates can be readily prepared by the reaction of the free phenolic compounds with sulfur trioxide complexed with an amine such as pyridine, trimethylamine, triethylamine, etc.
  • Sulfamates can be prepared by treating the, free phenolic compound with the desired amino or alkylamino or dialkylamino sulfamyl chloride in the presence of a suitable base such as pyridine.
  • Sulfate esters can be prepared by reaction of the free phenol with the desired alkanesulfonyl chloride in the presence of a suitable base such as pyridine.
  • this invention includes compounds containing phosphates at the phenol as well as dialkyl phosphates.
  • Phosphates can be prepared by reaction of the phenol with the appropriate chlorophosphate.
  • the dialkylphosphates can be hydrolyzed to yield the free phosphates.
  • Phosphinates are also claimed where the phenol is reacted with the desired dialkylphosphinic chloride to yield the desired dialkylphosphinate of the phenol.
  • the invention includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid useful as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
  • this invention includes quaternary ammonium salts of the compounds herein. These can be prepared by reacting the nucleophilic amines of the side chain with a suitably reactive alkylating agent such as an alkyl halide or benzyl halide.
  • the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgement of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
  • Effective administration of these compounds may be given at an effective dose of from about 0.1 mg/day to about 500 mg/day. Preferably, administration will be from about 1 mg/day to about 200 mg/day in a single dose or in two or more divided doses.
  • Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, parenterally (including intravenous, intraperitoneal and subcutaneous injections), and transdermally.
  • transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • the active ingredient in the formulations and methods of this invention is l-[4-(2-Azepan-lyl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-lH-indol-5-ol, also known as TSE-424, or a pharmaceutically acceptable salt thereof
  • the preferred daily dosage for oral delivery is from about 0.1 to about 50 mg, preferably from about
  • the active ingredient in the formulations and methods of this invention is 2-(4-Hydroxy-phenyl)-3 -methyl- 1 -(4-(2-piperidin- 1 -yl-ethoxy)-benzyl]- lH-indol- 5-ol, also known as ERA-923, or a pharmaceutically acceptable salt form thereof
  • the preferred daily dosage for oral delivery is from about 0.1 to about 200 mg, preferably from about 2.5 to about 100 mg per day.
  • Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
  • Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, macrocrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, macrocrystalline
  • Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • Solid oral formulations preferably in the form of a film coated tablet or capsule, useful for this invention include the active pharmacological agents disclosed herein in combination with carrier or excipient systems having the components: a) a filler and disintegrant component comprising from about 5% to about 82% by weight (wght) of the total formulation, preferably between about 30% and about 80% of the formulation, of which from about 4% to about 40% by weight of the total formulation comprises one or more pharmaceutically acceptable disintegrants; b) optionally, a wetting agent comprising from about 0.2 to about 5% of the composition (wght), such as selected from the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, sugar esters of fatty acids and glycerides of fatty acids; c) a fill
  • fatty acid esters e.g. sodium stearyl fumarate
  • fatty acids e.g. stearic acid
  • fatty alcohols e.g. glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates and sodium chloride; and d) optionally, a glidant comprising from about 0.1% to about 10% (wght) of the composition, the glidant selected from those known in the art, including from the group of silicon dioxide, talc, metallic stearates, calcium silicate, or metallic lauryl sulfates.
  • compositions described herein may be used in an uncoated or non- encapsulated solid form, preferably the final compositions are coated or encapsulated.
  • the pharmacological compositions may be optionally coated with a film coating, preferably comprising from about 0.3% to about 8% by weight of the overall composition.
  • Film coatings useful with the present formulations are known in the art and generally consist of a polymer (usually a cellulosic type of polymer), a colorant and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils and lubricants may be included in film coating formulations to impart certain characteristics to the film coat.
  • the compositions and formulations herein may also be combined and processed as a solid, then placed in a capsule form, such as a gelatin capsule.
  • the filler component listed above may utilize the filler or binder components known in the art for solid oral formulations.
  • Pharmaceutically acceptable fillers or binding agents selected from those known in the art including, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, or xylitol.
  • disintegrant agents may be selected from those known in the art, including pregelatinized starch and sodium starch glycolate.
  • Other useful disintegrants include croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate, clays (e.g.
  • veegum or xanthan gum cellulose floe
  • ion exchange resins or effervescent systems, such as those utilizing food acids (such as citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, and succinic acid) and an alkaline carbonate component (such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate, etc.).
  • the disintegrant(s) useful herein will comprise from about 4% to about 40% of the composition by weight, preferably from about 15% to about 35%, more preferably from about 20% to about 35%.
  • Some components may have multiple functions in the formulations of this invention, acting e.g. as both a filler and a disintegrant, such a component may be referred to as a filler disintegrant and its function in a specific formulation may be singular even though its properties may allow multiple functionality.
  • the pharmaceutical formulations and carrier or excipient systems herein preferably also contain an antioxidant or a mixture of antioxidants, most preferably ascorbic acid.
  • Other antioxidants which may be used include sodium ascorbate and ascorbyl palmitate, preferably in conjunction with an amount of ascorbic acid.
  • a preferable range for the antioxidant(s) is from about 0.5% to about 15% by weight, most preferably from about 0.5% to about 5% by weight.
  • formulations of this invention are pharmaceutical formulations containing a pharmaceutically effective amount of an active pharmacological agent and a carrier or excipient system comprising: a) a filler and disintegrant component comprising between about 50% and about 87% of the formulation, with from about 4% to about 40% of the formulation comprising one or more disintegrant agents; b) a wetting agent comprising between about 0.5% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; and d) a glidant comprising between about 0.1 % and about 5.5% of the formulation.
  • the percentages listed in the formulations above indicate percentages by weight of the total weight of the components listed from a) to d).
  • the formulations above also preferably contain an optional antioxidant component, preferably ascorbic acid, at a concentration of from about 0.5% to about 5.5% by weight of the formulation.
  • the formulations are also preferably contained within a pharmaceutically acceptable capsule, such as a gel capsule, or coated with a film coating comprising from about 0.3% to about 8% by weight of the formulation.
  • This invention also comprises a pharmaceutical carrier or excipient systems useful in pharmaceutical compositions utilizing as an active ingredient one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, as described herein.
  • These pharmaceutical carrier or excipient systems comprise, by weight: a) a filler and disintegrant component comprising between about 54% and about 80% of the formulation, with the disintegrant agent(s) therein comprising from about 4% to about 40% by weight of the overall formulation; b) a wetting agent comprising between about 0.55% and about 2.5% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; and d) a glidant comprising between about 0.1% and about 5.0% of the formulation.
  • the more preferred carrier or excipient systems above also optionally and preferably contain an antioxidant component, preferably ascorbic acid, at a concentration of from about 0.1% to about 5.0% by weight.
  • an antioxidant component preferably ascorbic acid
  • the carrier or excipient systems of this invention are those comprising: a) a filler and disintegrant component, as described above, comprising between about 50% and about 87% of the formulation, the disintegrant(s) therein comprising from about 25% to about 35% of the formulation, by weight; b) a wetting agent comprising between about 0.55% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; d) a glidant comprising between about 0.1% and about 5.5% of the formulation; and e) an antioxidant component, preferably ascorbic acid, at a concentration of from about 0.1% to about 5.5% by weight.
  • a filler and disintegrant component as described above, comprising between about 50% and about 87% of the formulation, the disintegrant(s) therein comprising from about 25% to about 35% of the formulation, by weight
  • Wet granulation of the formulations as described in Table 1 may be carried out by mixing the drug and ascorbic acid with a portion of the lactose, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate.
  • the sodium lauryl sulfate is dissolved in the water and used to granulate the mixture of powders in a high shear mixer.
  • the granulation is dried in a fluid bed dryer to a moisture of 2-3%.
  • the particle size of the dried granulation is controlled by passing through a mill equipped with knife-edged blades and using a 20- or 30-mesh screen.
  • the silicon dioxide and remaining lactose, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate are mixed with the milled granulation in a tumble- type mixer.
  • the final blend is prepared by adding magnesium stearate to the tumble- type mixer and mixing. Compression is carried out on a rotary tablet press using appropriate size tooling. Coating is performed in conventional coating pans and applying the coating suspension to achieve a suitable film coat.
  • a Amount in formula is adjusted for actual potency of TSE-424 as free base. Corresponding adjustment made with Lactose.
  • ERA-923 tablets are compressed to a tablet weight of up to 640 mg to achieve the target dose (up to 100 mg). Tablets may then be film coated.
  • a preferred carrier or excipient system for formulating a granulation of from about 2 to about 8% by weight of one of the active pharmacological agents of this invention, preferably about 5%, may be produced utilizing the carrier or excipient components on a weight percentage; lactose from about 32% to about 38%, microcrystalline cellulose from about 32% to about 38%, pregelatinized starch from about 12% to about 16%, ascorbic acid from about 1% to about 2%, sodium lauryl sulfate from about 1% to about 2%, sodium starch glycolate from about 4% to about 8%, silicon dioxide from about 0.1% to about 0.2% and magnesium stearate from about 0.3% to about 0.7%.
  • a formulation using TSE-424 as the active ingredient at a 5% granulation was prepared with the components below in a granulation part of components and a dry part.
  • TSE-424 tablet weight mg mg of film coat applied/tablet
  • This invention also provides novel pharmaceutical compositions utilizing as active ingredients one or more of the non-steroidal anti-estrogens or tissue selective estrogens or selective estrogen receptor modulators (SERMs) in question, such as tamoxifen, droloxifene, raloxifene or the others listed herein, along with one of the substituted indole compounds of this invention and one or more pharmaceutically acceptable carriers or excipients.
  • SERMs tissue selective estrogens or selective estrogen receptor modulators
  • Sprage-Dawley rats (240-260 grams) were divided into 4 groups: (1) Normal non-ovariectomized (intact); (2) Ovariectomized (ovex) vehicle treated; (3) Ovariectomized 17- ⁇ estradiol treated (1 mg/kg/day); and (4) Ovariectomized TSE- 424 treated (1 mg/kg/day). All animals were ovariectomized approximately 3 weeks prior to treatment. Each received 1 mg/kg/day of either 17- ⁇ estradiol sulfate or TSE- 424 suspended in distilled, deionized water with 1% tween-80 by gastric gavage. Vehicle treated animals received an appropriate volume of the vehicle used in the drug treated groups.

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Abstract

Cette invention concerne des méthodes permettant d'accroître l'activité d'oxyde nitrique-synthase chez des mammifères et la production d'oxyde nitrique. Ces méthodes consistent à administrer un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de ce composé. Dans la formule (I), Z est une fraction prise dans le groupe de (II) dans lequel R1 est pris dans H, OH ou dans les esters en C1-C12 des alkyl éthers en C1-C12, ou des halogènes; ou des éthers halogénés en C1-C4 comprenant un trifluorométhyl éther et un trichlorométhyl éther; R2, R3, R4, R5, et R6 sont H, OH ou des alkyl éther en C1-C12 , des halogènes, ou des éthers halogénés en C1-C4, cyano, alkyle en C1-C5, ou trifluorométhyle, à condition que quand R1 est H, R2 n'est pas OH; Y est une fraction selon (III) : R7 et R8 sont un alkyle ou sont concaténés pour former un anneau renfermant de l'azote éventuellement substitué.
PCT/US2001/021083 2000-07-06 2001-06-29 Methodes permettant d'accroitre l'activite d'oxyde nitrique- synthase WO2002003991A2 (fr)

Priority Applications (6)

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JP2002508445A JP2004502734A (ja) 2000-07-06 2001-06-29 一酸化窒素シンターゼ活性の増強方法
EP01950824A EP1296674A2 (fr) 2000-07-06 2001-06-29 Methodes permettant d'accroitre l'activite d'oxyde nitrique- synthase
BR0112360-2A BR0112360A (pt) 2000-07-06 2001-06-29 Método para aumentar a atividade da sintase de óxido nìtrico
CA002414111A CA2414111A1 (fr) 2000-07-06 2001-06-29 Methodes permettant d'accroitre l'activite d'oxyde nitrique- synthase
AU7178301A AU7178301A (en) 2000-07-06 2001-06-29 Methods for increasing nitric oxide synthase activity
MXPA02012890A MXPA02012890A (es) 2000-07-06 2001-06-29 Uso de compuestos de indol sustituidos para incrementar la actividad de oxido nitrico sintasa.

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US21618700P 2000-07-06 2000-07-06
US60/216,187 2000-07-06

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CA2414111A1 (fr) 2002-01-17
JP2004502734A (ja) 2004-01-29
CN1635885A (zh) 2005-07-06
EP1296674A2 (fr) 2003-04-02
AU7178301A (en) 2002-01-21
US20020022617A1 (en) 2002-02-21
BR0112360A (pt) 2003-05-06
MXPA02012890A (es) 2003-10-24
WO2002003991A3 (fr) 2002-07-04

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